Relationship between bleomycin and radiation-induced interstitial pneumonia and activation of serotonin degradation system and exploration of its treatment / 药学学报

Previously, we discovered that cells contain a 5-hydroxytryptamine (5-HT) degradation system (5DS), which includes 5-HT2A receptor (5-HT2AR), 5-HT synthase, and monoamine oxidase A (MAO-A). Among these, 5-HT2AR has the ability to regulate the expression of 5-HT synthase and MAO-A, and activation of 5DS causes upregulation of these proteins at the same time, resulting in the production of reactive oxygen species (ROS) in the mitochondria. In this study, we investigated the relationship between interstitial pneumonia (IP) and 5DS activation, as well as the therapeutic effect of inhibiting 5DS on IP. Animal models of bleomycin (BLM)-induced IP in mice and radiation (Rad)-induced IP in rats were established, and the models were treated with the 5-HT2AR antagonist sarpogrelate hydrochloride (SH), 5-HT synthesis inhibitor carbidopa (CDP), and their combination (SH∶CDP = 2∶1). The animal experiments were carried out in accordance with the regulations of the Animal Ethics Committee of China Pharmaceutical University. In the two IP models, immunohistochemistry staining and Western blot analysis showed that the expression of 5-HT synthase was significantly upregulated in all cells of lung tissue, while the expression of 5-HT2AR and MAO-A was most significantly upregulated in the macrophages. Treatment with SH or CDP significantly reduced pulmonary interstitial thickening, alveolar atrophy with collapse, massive macrophage infiltration and interstitial fibrosis in the two IP models, as measured by HE and Masson staining, and a combination of both almost eliminated the lung tissue lesions. Moreover, treatment with the combination of SH and CDP almost completely eliminated increased ROS and malondialdehyde levels, decreased superoxide dismutase activity, increased tumor necrosis factor-α and interleukin-1β levels, and upregulated nuclear factor-κB phosphorylation and α‍-smooth muscle actin, matrix metalloproteinase-2, and collagen expression. SH and CDP worked together to create a synergistic effect. The findings suggested that the activation of 5DS, as evidenced by increased 5-HT synthesis in all cells of lung tissue and increased 5-HT synthesis and degradation in macrophages, is probably related to the occurrence of IP and that inhibition of 5DS can effectively treat IP.

The role of renal 5-hydroxytryptamine synthesis and degradation in hyperglycemia-induced kidney injury / 药学学报

Hyperglycemic kidney injury (HKI) is a common complication of diabetic patients. We examined the relationship between HKI and the abnormal expression of 5-hydroxytryptamine (5-HT) system induced by hyperglycemia in type 2 diabetes mellitus (T2DM). In animal experiments, a T2DM model was established in mice by feeding a high-fat diet with intraperitoneal injection of streptozotocin. The mice were treated with the 5-HT2A receptor (5-HT2AR) antagonist sarpogrelate hydrochloride (SH) and 5-HT synthesis inhibitor carbidopa (CDP) (respectively or in combination). In cell culture experiments, human glomerular mesangial cells (HMC) were stimulated with D-glucose (D-Glu), and 5-HT2AR, 5-HT synthesis, and 5-HT degradation were inhibited by SH, CDP, or monoamine oxidase A (MAO-A) inhibitor clorgyline. Periodic acid-Schiff (PAS) staining and Masson staining, immunohistochemistry and Western blot, fluorescent probe, and enzyme linked immunosorbent assay (ELISA) and enzyme reagent were respectively used to detect histopathology, protein expression, intracellular reactive oxygen species (ROS), and biochemical indexes. The animal experiments were in accordance with the regulations of the Animal Ethics Committee of China Pharmaceutical University. The results showed that 5-HT2AR, 5-HT synthases, and MAO-A were expressed in glomerular basement membrane and kidney tubular epithelial cells of mouse kidney and HMC. The expression of these proteins was significantly up-regulated in T2DM mice or when HMC cells were exposed to high concentration of D-Glu. HKI, characterized by abnormal renal function, glomerular swelling, and glomerular basement membrane thickening and fibrosis, is closely associated with an increase in kidney 5-HT2AR, 5-HT synthesis, and 5-HT degradation. Among them, 5-HT2AR can mediate the expression of 5-HT synthases and MAO-A; MAO-A can catalyze the degradation of 5-HT to increase the production of mitochondrial ROS, leading to the phosphorylation of nuclear factor kappa B (NF-κB) with the production of inflammatory cytokines, and the up-regulation of matrix metalloproteinase-2 (MMP-2) and α-smooth muscle actin (α-SMA) with the production of collagens. SH and CDP can effectively treat HKI, and the combination of SH and CDP has a clear synergistic effect.

Relationship between fatigue caused by type 2 diabetes mellitus and 5-HT degradation in skeletal muscle / 药学学报

Fatigue is a common complication of type 2 diabetes mellitus (T2DM). We examined the relationship between T2DM fatigue and the skeletal muscle 5-hydroxytryptamine (5-HT) system. In animal experiments, a T2DM model was established in mice by feeding a high-fat diet with intraperitoneal injection of streptozotocin. The mice were treated with the 5-HT2A receptor antagonist sarpogrelate hydrochloride (SH) and the 5-HT synthesis inhibitor carbidopa (CDP) (separately and in combination). In cell culture experiments, C2C12 cells were stimulated with D-glucose, palmitic acid or 5-HT. 5-HT2AR, 5-HT synthesis and 5-HT degradation were inhibited by SH, CDP, or monoamine oxidase A (MAO-A) inhibitor. The animal experiments were in accordance with the regulations of the Animal Ethics Committee of China Pharmaceutical University. The results showed that 5-HT2AR, 5-HT synthase and MAO-A were expressed in mouse skeletal muscle and C2C12 cells. The expression of these proteins was significantly up-regulated in T2DM mice or when C2C12 cells were exposed to palmitic acid and D-glucose; palmitic acid was a stronger stimulant of their expression than D-glucose. Rotating rod experiments and biochemical index tests have shown that T2DM fatigue is associated with an increase in skeletal muscle 5-HT2AR, 5-HT synthesis and 5-HT degradation. 5-HT2AR mediates the expression of MAO-A and the synthesis of 5-HT, which indirectly regulates the degradation of 5-HT. MAO-A regulates cell inflammation, mitochondrial ROS production and membrane potential depolarization by mediating 5-HT degradation. MAO-A also inhibits the expression of peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1), carnitine palmitoyltransferase-1 (CPT1) and ATP synthase-6 (ATP6), thus inhibiting mitochondrial functions such as fatty acid β oxidation and ATP synthesis. SH and CDP can effectively treat T2DM fatigue, and can also reduce blood glucose and blood lipid, and the combination of SH and CDP has a clear synergistic effect.

Relationship between MnSOD polymorphisms and susceptibility of chronic poisoning exposed to manganism occupationally / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To study the relationship between polymorphisms of MnSOD and the susceptibility of chronic poisoning exposed to manganism occupationally.</p><p><b>METHODS</b>In a study of case-control, genotypes were determined by PCR-RFLP in 164 patients with chronic occupational mangamism poisoning and 328 controls with age- and sex-matched for MnSOD 9Ala-Val.</p><p><b>RESULTS</b>There was a significant difference in the frequency of MnSOD 9Ala-Val at V locus mutant allele between cases and controls (χ(2) = 15.225, P < 0.01, 95%CI = 1.43 ∼ 3.00). Individuals with the genotype VV had a 1.30 of risk increase of occupational chronic manganism poisoning compared with the the genotype AV or AA (OR = 2.30, 95%CI = 1.52 ∼ 3.49, P < 0.05).</p><p><b>CONCLUSION</b>The MnSOD polymorphisms may be related with the susceptibility to chronic occupational manganism poisoning, the risk of chronic occupational manganism poisoning increases in carriers with genotype VV at MnSOD 9Ala-Val locus.</p>

The prevalence and evolution of HIV drug-resistant strains in people who live with HIV/AIDS during HIV antiretroviral therapy in Shandong province / 中华预防医学杂志

<p><b>OBJECTIVE</b>To understand the prevalence and evolution of HIV drug-resistant strains in people who live with HIV/AIDS (PLWHA) during HIV antiretroviral therapy in Shandong province.</p><p><b>METHODS</b>Viral load testing was performed by using fluorescence real-time quantitative PCR (NucliSens EasyQ system) on 324 patients who were under HIV antiretroviral therapy (ART) over 1 year in Shandong province. HIV resistance testing was conducted on the samples with more than 1000 copies/ml by using genotypic resistance testing method established in our lab. We tested the samples from drug-resistant patients before and after treatment to analyze the evolution of HIV resistant strains.</p><p><b>RESULTS</b>The resistance rate for the patients under HIV ART over 1 year was 6.2% (20/324). The rate of drug-resistant mutation, but not resistant to ART was 0.6% (5/324). Nucleoside reverse transcriptase inhibitor (NRTIs) and non-NRTIs (NNRTIs) accounted for 93.1% (94/101) and protein inhibitors (PIs) accounted only 6.9% (7/101) of all mutations. M184V (48.0%, 12/25) and Y181C (32.0%, 8/25) were the most frequent mutations among 25 samples. Our research showed 20.0% (2/10) patients were resistant to primary ART and 1 patient was detected drug resistance in 6 months after ART treatment. HIV evolved from wild type to drug resistant virus, from low level to high level drug resistance, and from resistance to few to multiple drugs. In addition, interactions between mutations may influence the sensitivity of patients to other drug treatment.</p><p><b>CONCLUSION</b>The prevalence of HIV drug-resistant strains in Shandong province is still at a low level, but its evolution is complex.</p>

Survival analysis of 530 HIV infected former unsafe commercial blood and plasma donors / 中华预防医学杂志

<p><b>OBJECTIVE</b>To investigate HIV survival time and it's influencing factors among former commercial blood and plasma donors engaged in unsafe blood donation practices in China.</p><p><b>METHODS</b>HIV/AIDS cases from 8 counties (districts) in 4 provinces confirmed prior to January 24, 2006 related with former commercial blood and plasma donors were selected and data regarding infection, AIDS progression, death, and influencing factors were retrospectively collected.</p><p><b>RESULTS</b>In 530 cases of HIV infection, 334 (63.0%) cases had developed AIDS, 168 (50.3%) had received antiretroviral therapy (ART), and 152 (29.0%) had died. For the 530 cases, there was an average (10.1 +/- 1.8) years of observation from time of infection. Among 166 AIDS patients not receiving ART, average survival was 9.1 years (95% CI: 9.1 - 9.4), with an 8 year survival rate of 52.0%. Among 168 AIDS patients receiving ART, average survival was 12.1 years (95% CI: 11.9 - 12.3), with a 12-year survival rate of 80.0%. In 3 years of ART, average survival was longer in the treatment group as compared to the no treatment group with a hazard ratio for death of 12.2. Univariate analysis showed a significant difference (P < 0.05) in AIDS patient average survival based on gender, age, location, ART status, and baseline CD(4)(+) T cells count. Results from multivariate COX-regression showed that highly active ant iretroriral therapy (HAART) was the strongest protective factor for prolonging AIDS patients' survival (HR = 13.3, P = 0.00).</p><p><b>CONCLUSION</b>Although there are many factors influencing AIDS patients survival, intervention with HAART is the principle measure to prolong survival and decrease the risk of death.</p>

Study on the effect of treatment and the status of drug resistance among HIV/AIDS patients treated with highly active antiretroviral therapy in Shandong province / 中华流行病学杂志

<p><b>OBJECTIVE</b>To understand the effect of highly active antiretroviral therapy (HAART) on AIDS patients, and to explore the prevalence and the impact of HIV-1 drug resistance in Shandong province.</p><p><b>METHODS</b>2 cross-sectional studies were carried on in 2004 and 2005, to collect data on clinical symptoms and compliance of the AIDS patients with HAART through questionnaire. Informed-consent principle was followed to test on immunological, viral and laboratory index of them. HIV-1 drug genotype resistance by sequencing the gene of HIV-POL after RT-PCR was performed and analyzed.</p><p><b>RESULTS</b>31 AIDS cases with and. 27 AIDS cases without HAART, were studied. 83.3% and 64.5% of the AIDS patients with HAART showed that the CD4+ T cell count was rising to over 350/microl, in the first study (2004) and in the second (2005) study respectively but still 45.8% and 45.2% of AIDS patients under HAART in the 2 years showed a decreasing HIV load under the detected limit. However, these findings were showing remarkable difference when compared with the AIDS without HAART. 7 drug resistance gene sites were found in AIDS patients with HAART and in AIDS patients without HAART. The rate on high degree drug resistance mutation and total drug resistance rate of mutation of the former were higher remarkably than those of the latter.</p><p><b>CONCLUSION</b>Most of the AIDS patients with HAART met the purpose of rebuilding immunity and control of HIV,as well as alleviation of symptoms. Although the drug resistance stain appeared in Shandong,but had little effect on HAART. AIDS; Drug resistance; Highly active antiretroviral therapy</p>

Study on the incidence and spatiotemporal dynamic variation of hemorrhagic fever with renal syndrome in Shandong province / 中华流行病学杂志

<p><b>OBJECTIVE</b>To study the incidence and spatiotemporal dynamic variation of hemorrhagic fever with renal syndrome (HFRS) in Shandong province.</p><p><b>METHODS</b>According to surveillance data on HFRS epidemics and host animals, a 'contour area multifractal model' was estimated on the HFRS' incidence and multi-analysis model was applied to study spatiotemporal dynamic variation.</p><p><b>RESULTS</b>The process could be classified into 5 periods: 1st period (1974-1981) when HFRS was in completely natural focal state in Shandong, and the nature of focus was typical Apodemus type. 2nd period (1982-1986) indicated the process of expanding and merging of the Apodemus type focus in the southeastern part of Linyi district and the Rattus type focus was in the southern part of Jining city. 3rd period (1987-1990) indicated that through the expanding and merging of the two epidemic focuses,one mixed focus dominated by the Apodemus type had been formed in the hilly area of the southern and middle part of Shandong while another one dominated by the Rattus type in the Yellow River valley of the northwestern part of Shandong. 4th period (1991-1993) showed that the process of the spatial pattern of the mixed focus dominated by the Rattus type in Shandong. 5th period (1994-2004) referred to the spatial pattern of the mixed focus dominated by the Rattus became stabilized.</p><p><b>CONCLUSION</b>Evolution of the characteristics of HFRS focus in Shandong province experienced the following three processes: the simple Apodemus type and the simple Rattus type were seen separately to the mixed foci with the Apodemus type dominant and the Rattus dominant type coexisted and merged to the stable state of the mixed focus with Rattus as the dominant one.</p>

The epidemiological study on human immunodeficiency virus infection among paid blood donors living in Shandong provincial China Comprehensive Response Project Areas / 中华流行病学杂志

<p><b>OBJECTIVE</b>To understand the current epidemic situation and high risk factors of human immunodeficiency virus (HIV) infection among paid blood donors living in Shandong provincial China Comprehensive Response (CARES) Project Areas.</p><p><b>METHODS</b>All residents between 20 to 60 years old were selected from one or several counties in August 2003.</p><p><b>RESULTS</b>There were 19 HIV(+) infections among 661 subjects interviewed. HIV prevalence rate among paid blood donors was higher (3.98%) than that of others (0.48%) while HIV prevalence rate was higher in plasma donors (7.24%) than that in both plasma and full blood donors (2.90%). There was no infections identified in full blood donors. Donors who donated blood during 1994 - 1995 had a higher prevalence rate (7.07%) than those who started donation after 1995 and those began donation before 1993 (0.99%). The rate of condom use was lower among paid blood donors (13.72%) than that of others. There was a lower rate of voluntary HIV testing among paid blood donors than that of others.</p><p><b>CONCLUSION</b>The main high risk population of HIV infection were paid donors in CARES Project Areas, whose risk factor was plasma donation and were infected mainly before 1995. Both the rate of condom use and HIV testing were all very low, indicating that they knew little on HIV/AIDS and paid less attention to self-proctection. It is necessary to enhance HIV/AIDS health education and behavior intervention on paid blood donors.</p>

Study on the molecular epidemiology of people infected with human immunodeficiency virus-1 in Shandong province / 中华流行病学杂志

<p><b>OBJECTIVE</b>To study the distribution of human immunodeficiency virus-1 (HIV-1) strains subtypes in Shandong province and to study their source in order to predict the epidemic trend.</p><p><b>METHODS</b>Epidemiological investigation was made and 93 DNA fragments of HIV-1 env, gag, tat gene were amplified by nested polymerase chain reaction from people infected with HIV-1, in 2002 - 2003. Their C2-V3, P17/P24, 1st exon of tat and adjacent region were sequenced.</p><p><b>RESULTS</b>Sequence analysis showed that there were 7 HIV-1 strains or circulating recombinant forms (CRFs), B' (n = 71), CRF01-AE (n = 9), CRF07-BC (n = 3), CRF08-BC (n = 3), B (n = 2), C (n = 2), CRF02-AG (n = 2). B' strains was the predominant which, covered 10 cities and 4 kinds of population including blood donors, blood receivers, spouses of the infected people and clients of the sex workers. CRF07-BC, CRF08-BC strains were identified in 5 cities, mainly from injecting drug users. CRF01-AE and other strains were found distributed in developed cities, among sex workers.</p><p><b>CONCLUSION</b>There were many kinds of subtypes and CRFs of HIV and their genomes which generated obvious variation in Shandong province, suggesting that they might facilitate the spread of the disease in Shandong province.</p>

Molecular analysis of hantavirus isolated from Shandong province / 中华实验和临床病毒学杂志

<p><b>OBJECTIVE</b>To compare the molecular characteristics of hantaviruses isolated from Shandong province by using PCR typing and nucleotide sequencing.</p><p><b>METHODS</b>Total cellular RNA was extracted from hantaviruses infected Vero E6 cells, viral cDNA was amplified by polymerase chain reaction. PCR products of partial M Segments of 4 strains of hantaviruses were sequenced. Cross neutralization tests were performed.</p><p><b>RESULTS</b>Four strains of hantavirus isolated from Rottus in Shandong province were SEO like viruses. The homology between Shandong isolates and other SEO like viruses was high at both amino acid and nucleotide levels. The homology among those 4 strains of hantaviruses was 98%.</p><p><b>CONCLUSIONS</b>The SEO like hantaviruses were more conserved than other hantaviruses. The homology of SEO like hantaviruses isolated from Shandong province was as high as 98% at nucleotides level, though they were isolated at more than 10-year intervals.</p>